S204: SAFETY AND TOLERABILITY OF CAEL-101, AN ANTI-AMYLOID MONOCLONAL ANTIBODY, COMBINED WITH ANTI-PLASMA CELL DYSCRASIA THERAPY IN PATIENTS WITH LIGHT-CHAIN AMYLOIDOSIS: 18-MONTH RESULTS OF A PHASE 2 STUDY
Authors: Jason Valent, Michaela Liedtke, Jeffrey Zonder, Maria Angelica Molina, Chandrasekhar Udata, Juliana Ianus, John Tripptree, Julia Catini, C Cristina Quarta
Journal: HemaSphere (2023)

Background: Light-chain (AL) amyloidosis is a rare, systemic disease caused by plasma cell dyscrasia (PCD). Immunoglobulin light chains misfold and deposit in organs, primarily the heart, as insoluble amyloid fibrils. The extent of heart involvement is a major indicator of patient survival. Current therapies target PCD to halt fibril formation but do not treat existing fibrils in organs. CAEL-101 is a novel, investigational, potentially first-in-class therapy to remove these fibrils from organs. Aims: To present safety, tolerability, and biomarker data for 18 months of treatment with CAEL-101, administered initially with cyclophosphamide-bortezomib-dexamethasone (CyBorD) ± daratumumab. Methods: Adult patients with AL amyloidosis (European Modification of Mayo Stage I-IIIa) and measurable hematologic disease were eligible for this ongoing, open-label, phase 2 study (NCT04304144). Other forms of amyloidosis and multiple myeloma were excluded. CAEL-101 ≤1000 mg/m2 was administered with anti-PCD therapy ± daratumumab as directed by the investigator. In addition to safety assessments, cardiac response was assessed by change over time in N-terminal pro-brain natriuretic peptide (NT-proBNP). Results: Patients (N=25; mean age 65 years; 72% male) with Mayo Stage I (n=2; 8%), II (n=19; 76%), and IIIa (n=4; 16%) AL amyloidosis were enrolled to be treated with CAEL-101. All patients experienced treatment-emergent adverse events (TEAEs), 6 (24%) experienced TEAEs possibly related to CAEL-101, 15 (60%) experienced ≥1 adverse event of ≥Grade 3 severity, and 13 (52%) experienced ≥1 serious adverse event. By 18 months, 9 patients had discontinued the study: 1 case each of adverse event, death, and heart and kidney transplant, and 2 cases each of withdrawal by patient, heart transplant, and physician decision. After 18 months of CAEL-101 treatment, 5/22 (23%) cardiac-evaluable patients (baseline NT-proBNP >332 ng/L) were responders (>30% NT-proBNP decrease and more than 300 ng/L decrease, if baseline NT-proBNP ≥650 ng/L), 11 (50%) were stable (neither response nor progression), and 1 (5%) showed cardiac disease progression (>30% increase and ≥300 ng/L increase from baseline in the absence of eGFR decline of ≥25%); data for 5 patients (23%) were missing. Cardiac response over time is shown in the Figure below and persisted even after cessation of anti-PCD treatment. Summary/Conclusion: Currently enrolled patients have been treated for ≥18 months and CAEL-101 was generally well tolerated without evidence of organ toxicity. Long-term safety evaluation of CAEL-101 continues in this study. Most TEAEs were mild to moderate. A phase 3 program has commenced to study the efficacy and safety of CAEL-101 in cardiac AL amyloidosis European Modification Mayo Stages IIIa and IIIb.Keywords: AL amyloidosis, Treatment, Antibody